Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

The metabolic effects of long term exercise in Type 2 Diabetes patients

Introduction: The effectiveness of physical exercise in the management of diabetes mellitus type 2 is well established. The purpose of this investigation was to evaluate the effect of long term exercise on glycemic and metabolic control measured after eight months in contrast to patients who had ceased their training after four months. Methods: After an effective 4 months' strength training or endurance training period, ten patients (5 male and 5 female, mean age ± SE:57.1 ± 1.6 yr) were randomised to a further 4 months of combined endurance and strength training, while a control group of 10 patients (5 male and 5 female, mean age ± SE:56. 9± 1.6 yr) ceased training. Results: Long term glycemic control improved and HbA1C values fell from 6.9 ± 0.4 to 6.2 ± 0.2 in active patients and increased from 7.5 ± 0.4 to 8.7 ± 0.6 in control patients (p = 0.002). Baseline levels of total cholesterol significantly decreased in training group (205.5 mg/dl ± 14.1 to 177.5 ± 13.3) and increased in controls (185.9 ± 14.1 to 220.2 ± 15.8) [p = 0.004]. In addition, significant decreases in LDL-cholesterol and triglyceride levels (both p < 0.05) were observed in the training group compared to controls. Conclusion: This study showed that in addition to a 4 month training period, continuation of training proved highly beneficial with further reductions in fasting blood glucose, HbA1C, total cholesterol, LDL-cholesterol, triglyceride, and an elevation in HDL-cholesterol concentrations in diabetes mellitus type 2 patients, thus resulting in a reduced atherogenic lipid profile. In contrast, patients who ceased training after 4 months developed an atherogenic lipid profile and a worsened glycemic control. The results of this study indicate that long term exercise plays an important role in the treatment of diabetes mellitus type 2 and may protect against the development of cardiovascular diseases

Increased C282Y heterozygosity in gestational diabetes

Background. Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism that is characterized by excess accumulation of iron in various organs and often leads to diabetes mellitus (DM). To study whether mutations in the hemochromatosis gene (HFE) could be a risk factor for the development of gestational diabetes mellitus (GDM), the prevalence of HFE mutations in patients with GDM was compared to that of healthy pregnant controls. Methods: GDM was diagnosed in 208 of 2,421 pregnant woman screened between the 24th and 28th week of gestation over a period of 18 months. Patients and 170 matched control subjects were screened for the HFE gene mutations C282Y and H63D. Results: In North and Central European GDM patients, the allele frequency of the C282Y mutation (7.7%) was higher than in pregnant controls (2.9%; p = 0.04), while the frequency of the H63D mutation was not different (p = 0.45). Three patients with GDM were homozygous for H63D (3.1%), 1 patient was homozygous for C282Y (1.0%), 2 patients were compound heterozygous (2.0%) and 26 were heterozygous [11 C282Y (11.2%) and 15 H63D (15.3%)]. C282Y and H63D allele frequencies were not different between controls and GDIVI patients of Southern European or non-European origin. Irrespective of the HIFE-mutation status, serum ferritin levels were increased in patients with GDM compared to healthy pregnant controls (p = 0.01), while transferrin saturation was similar in both groups. Conclusions: In North and Central European patients with GDM, the C282Y allele frequency is higherthan in healthy pregnant women, suggesting a genetic susceptibility to the development of GDM. Copyright (c) 2005 S. Karger AG, Basel

Effects of progressive strength training on muscle mass in type 2 diabetes mellitus patients determined by computed tomography

Objective: To examine the effect of a 4-month progressive strength training program on muscle and fat mass assessed by computed tomography (CT) in type 2 diabetes mellitus (T2DM) patients, and to assess the relationships of changes in muscle cross-section area (CSA) with glycaemic control. Methods: Twenty adults (mean age ± SE: 56.4 ± 0.9 a) with T2DM participated in a supervised strength training program for 4 months 3 days/week. Muscle and fat areas of the quadriceps muscle were estimated by CT volumetry before and immediately after the training. Glycaemic (HbA1c) and anthropometric (BMI, skinfolds) measurements were assessed at 0 and 4 months, respectively. Results: After strength training, muscle strength increased significantly in all measured muscle groups. Quadriceps size (CSA of the muscle) was increased by 2.4% (from 7.99 ± 0.3 cm to 8.18 ± 0.3 cm, p = 0.003) for the right extremity, 3.9% (from 8.1 ± 0.4 cm to 8.41 ± 0.5 cm, p = 0.04) for the left side. Fat tissue CSA reduced from 0.66 ± 0.1 cm to 0.56 ± 0.12 cm for the right leg (15.3% reduction) and from 0.58 ± 0.12 cm to 0.37 ± 0.13 cm for the left leg (35.8% reduction), resulting in a mean fat CSA reduction of 24.8%. Fat mass assessed by skin folds was significantly reduced and lean body mass was significantly increased. The change in muscle CSA was not correlated with the changes in HbA1c or muscle strength. Conclusions: Strength training significantly improves both muscle mass and the muscle to fat ratio in T2DM. However, changes in muscle observed with computed tomography were not related to changes observed in HbA1c with training

Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1):24 week results from a multicentre, double-blind, phase 3, randomised controlled trial

Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA1cbetween ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1cafter 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1cwas 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1ccompared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p&lt;0·0001] and for dapagliflozin 10 mg vs placebo was −0·45% [−0·58 to −0·31; p&lt;0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. Interpretation Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. Funding AstraZeneca and Bristol-Myers Squibb